Fig. 1: The Link between the UPS and NDs. The UPS represents a key process for protein degradation, involving ubiquitinating enzymes (E1, E2, and E3) and the 26S proteasome.

The UPS can be divided into two main steps: ubiquitination and protein degradation. During the ubiquitination process, a multistep cascade reaction occurs, starting with E1 enzymes utilizing ATP hydrolysis to generate a thioester bond between the C-terminal of ubiquitin and a cysteine residue in the active catalytic site of E1 enzymes. The activated ubiquitin is then transferred to E2 enzymes, forming a thioester bond between the E2 enzymes and ubiquitin. Finally, the charged E2 enzymes work in conjunction with E3 enzymes to transfer the activated ubiquitin to the misfolded protein substrate. The ubiquitin-tagged protein is then directed to the active center of the proteasome for degradation. On the other hand, DUBs play a crucial role in the UPS by removing ubiquitin tags from substrate proteins. In neurodegenerative diseases, the dysregulation of DUBs leads to the accumulation of misfolded proteins, which aggregate and become intracellular neurotoxins. This process ultimately results in neuronal death and the manifestation of various pathological characteristics associated with neurodegenerative diseases. UPS Ubiquitin-Proteasome System, NDs Neurodegenerative Diseases, E1 ubiquitin-activating enzymes, E2 ubiquitin-conjugating enzymes, E3 ubiquitin ligases, DUBs deubiquitinating enzymes.